The goal of this project is to develop the next generation of targeted T-cells with chimeric antigen receptors (CARs) for use in carcinomas and hematologic malignancies. CARs are now beginning to show activity in a number of pilot clinical trials and they have significant potential for therapy of many cancers that are currently incurable, however two issues have emerged that provide a barrier to rapid progress in the field: 1) available preclinical models have not accurately predicted the safety of CARs, and unexpected toxicities from cytokine release and tissue damage have been reported in recent trials; 2) high costs and long lead times required for vector production have slowed the clinical application of T cells expressing CARs, and prevent a facile and iterative approach to optimize CAR design and determine the optimal target structures on tumor cells. This is currently a major problem to the field, as our preliminary data has conclusively demonstrated that CARs have potent activity in a pilot clinical trial. Our preliminary data further establishes that T lymphocytes can be efficiently modified by mRNA electroporation without integration-associated safety concerns, and that infusions of RNA CAR T cells mediate robust antitumor effects in preclinical humanized models with disseminated tumor xenografts. Thus, this new platform affords the possibility of rapidly testing potent RNA CARs for antitumor activity, and in the event of toxicity, limiting off-target exposure by discontinuing CAR administration. Because late relapses due to tumor escape variants in pre-clinical models have been identified, it will be important to test combinations of CAR T cells to augment antitumor effects and prevent recurrence. The theme of the project remains essentially the same from the previous grant and our new specific aims are designed to: (1) enhance the delivery and trafficking of CARs using mRNA electroporated T cells; (2) optimize the cell used for CAR therapy and understand the mechanisms that lead to enhanced persistence; and (3) define whether combination CARs improve antitumor activity and decrease the emergence of resistant tumor. In summary, these overlapping studies will test the central hypothesis that multiple CARs (i.e., a CAR fleet) will improve CAR immunotherapy compared to therapy with monoclonal CARs. Furthermore, these studies will establish the safety and feasibility of increasing the therapeutic index of T cells engineered to express powerful activation domains without the associated safety concerns of integrating viral vectors.

Public Health Relevance

Most cancers in adults are currently considered incurable if they are not completely removed by surgery. This project is testing methods to modify lymphocytes so that they can kill tumors efficiently, safely, and specifically. The approach includes experiments designed to develop new approaches to test engineered lymphocytes for optimal targeting to tumors, and conducting new animal experiments to widen the number of targets attacked on tumors in order to decrease or eliminate the probability of developing tumor resistance. The results and broad conclusions from these studies will be used to design future clinical trials as an improved and less toxic form of cancer therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
4R01CA120409-10
Application #
9131521
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2006-04-01
Project End
2017-07-31
Budget Start
2016-08-01
Budget End
2017-07-31
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Ruella, Marco; Klichinsky, Michael; Kenderian, Saad S et al. (2017) Overcoming the Immunosuppressive Tumor Microenvironment of Hodgkin Lymphoma Using Chimeric Antigen Receptor T Cells. Cancer Discov 7:1154-1167
Liu, Xiaojun; Jiang, Shuguang; Fang, Chongyun et al. (2017) Novel T cells with improved in vivo anti-tumor activity generated by RNA electroporation. Protein Cell 8:514-526
Hu, Biliang; Ren, Jiangtao; Luo, Yanping et al. (2017) Augmentation of Antitumor Immunity by Human and Mouse CAR T Cells Secreting IL-18. Cell Rep 20:3025-3033
Ren, Jiangtao; Liu, Xiaojun; Fang, Chongyun et al. (2017) Multiplex Genome Editing to Generate Universal CAR T Cells Resistant to PD1 Inhibition. Clin Cancer Res 23:2255-2266
Tchou, Julia; Zhao, Yangbing; Levine, Bruce L et al. (2017) Safety and Efficacy of Intratumoral Injections of Chimeric Antigen Receptor (CAR) T Cells in Metastatic Breast Cancer. Cancer Immunol Res 5:1152-1161
Ren, Jiangtao; Zhang, Xuhua; Liu, Xiaojun et al. (2017) A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 8:17002-17011
Ruella, M; Kenderian, S S; Shestova, O et al. (2017) Kinase inhibitor ibrutinib to prevent cytokine-release syndrome after anti-CD19 chimeric antigen receptor T cells for B-cell neoplasms. Leukemia 31:246-248
Kawalekar, Omkar U; O'Connor, Roddy S; Fraietta, Joseph A et al. (2016) Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. Immunity 44:380-90
Fesnak, Andrew D; June, Carl H; Levine, Bruce L (2016) Engineered T cells: the promise and challenges of cancer immunotherapy. Nat Rev Cancer 16:566-81
Liu, Xiaojun; Ranganathan, Raghuveer; Jiang, Shuguang et al. (2016) A Chimeric Switch-Receptor Targeting PD1 Augments the Efficacy of Second-Generation CAR T Cells in Advanced Solid Tumors. Cancer Res 76:1578-90

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